PROJECT SUMMARY Lung cancer remains the most common cause of cancer-related deaths in the United States. Lung cancer growth, invasion, and metastasis require angiogenesis; however, current anti-angiogenesis therapies offer dramatic but short-lived effects on tumor growth and are limited by nearly universal systemic vascular side effects. Our preliminary data suggest that endothelial autophagy is required in vitro for secretion of interleukin- 6 (IL-6), known to promote pathologic angiogenesis, and in vivo for tumor growth. Accordingly, we hypothesize that endothelial autophagy is a targetable process required for pathological states such as tumor angiogenesis but not for normal vascular homeostasis. Along these lines, our Specific Aims are to:1) Determine the mechanism of autophagy-mediated secretion of angiogenic factors by lung endothelium in vitro; 2) Determine the lung tumor requirement for autophagy-mediated secretion of angiogenic factors by the pulmonary endothelium in vivo; and 3) Compare the autophagic activity of endothelium within human primary lung tumors with that of endothelium in histologically normal lung remote from tumors. We will use molecular and pharmacologic interventions as well as live cell imaging, to explore distinct vesicle trafficking pathways and determine the mechanism of secretory autophagy of IL-6 by lung endothelial cells. We will also utilize an endothelial-specific conditional deletion of Atg5 to test the role of endothelial autophagy in supporting lung orthotopic and metastatic growth of isogenic tumor cell lines of diverse origin. To provide a translational link to the human condition we will isolate microvascular endothelium from fresh human non-small cell lung cancer tumors and adjacent and remote lung tissue, and determining differential activation of autophagy ex vivo. If the outcome is as expected, we will have uncovered a specific vulnerability inherent to tumor angiogenesis that could lead to novel treatment strategies against lung cancer. The candidate has a sustained track record of research in vascular biology, and this K01 award will expand his technical skills and expertise in the field of cancer biology. His mentoring team and advisory committee are composed of successful scientific mentors with expertise in cancer and vascular biology, autophagy, vesicular transport, and cancer microenvironment. In addition, this K01 is geared to accomplishing scientific independence and will expose him to specific career development activities in part through emphasis on training underrepresented minority investigators.